Aims: GLP-1 receptor agonists (GLP-1RA) have become a cornerstone of primary care for the treatment of obesity and diabetes and are typically recommended to be in conjunction with lifestyle modifications. However, limited evidence exists on whether lifestyle interventions such as intermittent fasting affect the efficacy of GLP-1RAs in promoting weight loss and improving glycemic control.
Methods: Male diet-induced obesity (DIO) mice underwent alternate-day fasting (ADF) with or without the GLP-1RA dulaglutide (Dula) for 8 weeks. Dulaglutide was injected via subcutaneous injection every 4 days. Phenotypic monitoring of body weight, energy expenditure, temperature, blood glucose, glucose and insulin tolerance tests were conducted.
Results: The combination of ADF and Dul produced significantly greater reductions in body weight compared with ADF alone, primarily driven by reductions in white adipose tissue, and an overall increase in lean mass. Mice treated with ADF+Dula showed reduced overall energy expenditure relative to ADF alone. Blood glucose was markedly reduced in both fed and fasted states in the ADF+Dula group, which also demonstrated improved glucose tolerance. Interestingly, an ex vivo repeated glucose-stimulated insulin secretion assay revealed that displayed a lower, though non-significant, trend towards a reduction in insulin secretion in isolated islets from the ADF+Dula mice.
Conclusion: These findings demonstrate for the first time that intermittent fasting can interact with GLP-1RA therapy to enhance reduction in body weight and blood glucose in diet-inducted obesity. the combined effects appear largely independent of reductions in lean mass and insulin sensitivity. Future studies are warranted to understand the underlying molecular mechanisms.